The present invention relates to an amantadine salt of montelukast and the uses thereof.
EP 480717 discloses certain substituted quinoline compounds including [R-(E)]-1-[[[1-[3-[2-[7-chloro-2-quinolinyl] ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid sodium salt (now more commonly known as, and referred to herein as montelukast sodium) of the formula (1).

Montelukast sodium is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT1 receptor. It is useful as an anti-asthmatic, anti-allergic, anti-inflammatory and/or cytoprotective agent.
Montelukast sodium is indicated for the prophylaxis and chronic treatment of asthma in adults and pediatric patients 6 years of age and older. The dosage for adolescents and adults 15 years of age and older is typically one 10-mg tablet daily to be taken in the evening.
Montelukast sodium is a hygroscopic white to off-white powder, which is freely soluble in ethanol, methanol, and water and practically insoluble in acetonitrile.
The reported synthesis of montelukast sodium in EP 480717 proceeds through the corresponding methyl ester. The methyl ester of montelukast is hydrolyzed to the free acid (montelukast acid of the formula 2)
and the later converted directly to the corresponding sodium salt.
This process is not particularly suitable for large-scale production because it requires tedious chromatographic purification of the methyl ester intermediate and/or the final product, and the product yields are low.
WO Patent Application 95/18107 discloses an improved process for the preparation of crystalline montelukast sodium salt, which comprises the generation of a dilithium dianion of 1-(mercaptomethyl) cyclopropaneacetic acid followed by condensation with 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-methanesulfonyloxypropyl)phenyl)-2-propanol to afford the montelukast acid which is then converted, via the dicyclohexyl amine salt of montelukast (formula 3),
to its corresponding sodium salt. The obtained sodium salt is further crystallized from a mixture of toluene:acetonitrile to obtain crystalline montelukast sodium.
The montelukast dicyclohexyl amine salt is reported to be a useful intermediate for the purification of the crude montelukast acid before its conversion to the desired sodium salt. In the crystalline state, the montelukast dicyclohexylamine salt was obtained in two polymorphic modifications.
US Application Publication 2005-0107612 discloses a process for preparation of montelukast sodium comprising:                (i) providing a solution of starting montelukast free acid in a halogenated solvent, aromatic solvent, or mixtures thereof;        (ii) treating said solution with a source of sodium ion to convert said montelukast free acid into a sodium salt of montelukast;        (iii) adding a cyclic or acyclic hydrocarbon solvent to said solution thereby precipitating said sodium salt of montelukast.        
It also teaches that montelukast acid may be generated in situ from an amine salt of montelukast, whereby specifically mentioned amines include tert. butylamine and phenyl ethylamine. The tert.butylamine salt of montelukast is described in example 6.
The tert.butylamine salt of montelukast is also described in US application 2005-0234241.
PCT patent application W02004-108679 discloses another process wherein purification of montelukast proceeds via its dicyclohexylamine salt.
PCT patent application W02005-074935 discloses several forms of montelukast free acid and a process for preparing montelukast free acid. The process generally includes a step of liberating montelukast free acid from its salt. One of the specifically mentioned salts (and the only amine salt) is dicyclohexylamine salt.
While the above disclosed amine salts of montelukast can be useful for isolation and purification of the montelukast acid before its conversion to montelukast sodium, it would be desirable to find another salt to facilitate the isolation and purification. Additionally, it would be desirable to find a pharmaceutically acceptable salt, as the known amine salts of montelukast suffer from the disadvantage that the amine moieties are generally not pharmaceutically acceptable.